TODO:

Preambule

Load data

## 
## DETECTIVE_Ph2 DETECTIVE_Ph3        GATHER 
##           329           522           251
## TQ doses in efficacy analyses:
## 
## No Radical Cure            PQ15           TQ100           TQ300            TQ50 
##             186             265              56             482              55 
##           TQ600 
##              56
## [1] 482
## [1] 7.692307
## [1] 4.929577
## 27 patients were lost to follow-up before 1 month
## 39 patients were lost to follow-up before 4 months
## 125 patients were lost to follow-up before 6 months
## 
## No Radical Cure            PQ15           TQ100           TQ300            TQ50 
##             182             257              56             469              54 
##           TQ600 
##              55
## A total of 634 patients received TQ in the efficacy population with doses varying from 0.5 to 14.3 mg/kg
## 
##   0   1 
## 775 298
## 
##   0   1 
## 713 360
## Warning: NAs introduced by coercion

Data summaries

Table 1

##             tqcat tqmgkgtot
## 1 No radical cure  0.000000
## 2              PQ  0.000000
## 3     [0.01,3.75)  1.987331
## 4     [3.75,6.25)  4.893435
## 5     [6.25,8.75)  6.936322
## 6       [8.75,15] 10.696189
##             tqcat mean   n total
## 1 No radical cure 55.5 101   182
## 2              PQ 22.2  57   257
## 3     [0.01,3.75) 33.7  57   169
## 4     [3.75,6.25) 21.5  79   368
## 5     [6.25,8.75)  7.4   4    54
## 6       [8.75,15]  0.0   0    43
## mean age:
##             tqcat age
## 1 No radical cure  35
## 2              PQ  36
## 3     [0.01,3.75)  37
## 4     [3.75,6.25)  36
## 5     [6.25,8.75)  36
## 6       [8.75,15]  33
## SD age:
##             tqcat  age
## 1 No radical cure 14.1
## 2              PQ 14.4
## 3     [0.01,3.75) 13.4
## 4     [3.75,6.25) 14.2
## 5     [6.25,8.75) 17.2
## 6       [8.75,15] 14.4
##             tqcat sex
## 1 No radical cure  50
## 2              PQ  77
## 3     [0.01,3.75)  43
## 4     [3.75,6.25)  95
## 5     [6.25,8.75)  24
## 6       [8.75,15]   9
##             tqcat sex
## 1 No radical cure  27
## 2              PQ  30
## 3     [0.01,3.75)  25
## 4     [3.75,6.25)  26
## 5     [6.25,8.75)  44
## 6       [8.75,15]  21
##             tqcat weight
## 1 No radical cure     62
## 2              PQ     63
## 3     [0.01,3.75)     72
## 4     [3.75,6.25)     63
## 5     [6.25,8.75)     51
## 6       [8.75,15]     57
##             tqcat weight
## 1 No radical cure   12.0
## 2              PQ   12.1
## 3     [0.01,3.75)   20.1
## 4     [3.75,6.25)    8.7
## 5     [6.25,8.75)   13.3
## 6       [8.75,15]    7.3
##              
##               No radical cure  PQ [0.01,3.75) [3.75,6.25) [6.25,8.75) [8.75,15]
##   Brazil                   55  80          61         105           6         3
##   Cambodia                 10   8           0          16           2         0
##   Colombia                  0   5           0          11           0         0
##   Ethiopia                 14  13           0          18           7         0
##   India                     9   5          21           8           4         7
##   Peru                     62  91          56         136          21        18
##   Philippines               1   2           0           3           0         0
##   Thailand                 31  38          31          46          10        15
##   Vietnam                   0  15           0          25           4         0
##              
##               No radical cure PQ [0.01,3.75) [3.75,6.25) [6.25,8.75) [8.75,15]
##   Brazil                   30 31          36          29          11         7
##   Cambodia                  5  3           0           4           4         0
##   Colombia                  0  2           0           3           0         0
##   Ethiopia                  8  5           0           5          13         0
##   India                     5  2          12           2           7        16
##   Peru                     34 35          33          37          39        42
##   Philippines               1  1           0           1           0         0
##   Thailand                 17 15          18          12          19        35
##   Vietnam                   0  6           0           7           7         0
##             tqcat logpara0.0% logpara0.25% logpara0.50% logpara0.75%
## 1 No radical cure          30         2173         5470        11856
## 2              PQ         104         1712         4697        10430
## 3     [0.01,3.75)         129         1447         4320         9456
## 4     [3.75,6.25)         102         1431         4174        10101
## 5     [6.25,8.75)         151         1961         5507        12111
## 6       [8.75,15]         200         1692         6143        13313
##   logpara0.100%
## 1         66010
## 2         87380
## 3         51175
## 4         99604
## 5         80535
## 6         56100
##             tqcat hbday0.1 hbday0.2
## 1 No radical cure     12.9      1.5
## 2              PQ     13.0      1.6
## 3     [0.01,3.75)     12.9      1.8
## 4     [3.75,6.25)     13.2      1.6
## 5     [6.25,8.75)     12.3      1.8
## 6       [8.75,15]     12.6      1.8

PK data plot

For supplementary materials

## Rows: 5248 Columns: 18
## ── Column specification ────────────────────────────────────────────────────────
## Delimiter: ","
## chr (11): #ID, TIME, AMT, ODV, LNDV, AGE, SEX, BW, ACT, COUNTRY, PID
## dbl  (7): MDV, BLQ, CMT, EVID, TYPE, VOMIT, STUDY
## 
## ℹ Use `spec()` to retrieve the full column specification for this data.
## ℹ Specify the column types or set `show_col_types = FALSE` to quiet this message.
## there are a total of 4389 concentrations above LOQ in 718 patients

Kaplan Meier time to recurrence

## [1] 182 257 169 368  54  43

##              
##               No radical cure  PQ [0.01,3.75) [3.75,6.25) [6.25,8.75) [8.75,15]
##   Brazil                   55  80          61         105           6         3
##   Cambodia                 10   8           0          16           2         0
##   Colombia                  0   5           0          11           0         0
##   Ethiopia                 14  13           0          18           7         0
##   India                     9   5          21           8           4         7
##   Peru                     62  91          56         136          21        18
##   Philippines               1   2           0           3           0         0
##   Thailand                 31  38          31          46          10        15
##   Vietnam                   0  15           0          25           4         0
## Range of mg/kg weights:
## [1]  0.55 14.29
## Median number of methb measurements is 12 (range 2 to 19)
## 
##   0   1 
## 775 298
##                  
##                     0   1
##   No radical cure  81 101
##   PQ              200  57
##   [0.01,3.75)     112  57
##   [3.75,6.25)     289  79
##   [6.25,8.75)      50   4
##   [8.75,15]        43   0
##         Dose (mg) Rec 4 mths (%)     n
## 1 No radical cure           55.5 182.0
## 2              PQ           22.2 257.0
## 3     [0.01,3.75)           33.7 169.0
## 4     [3.75,6.25)           21.5 368.0
## 5     [6.25,8.75)            7.4  54.0
## 6       [8.75,15]            0.0  43.0

CYP2D6

## 
## FALSE  TRUE 
##   716   384
##          
##             0 0.5   1 1.5   2
##   *1/*1     0   0   0   0 407
##   *1/*10    0   0   0  56   0
##   *1/*17    0   0   0  34   0
##   *1/*3     0   0   3   0   0
##   *1/*4     0   0  62   0   0
##   *1/*41    0   0   0  27   0
##   *1/*5     0   0  24   0   0
##   *1/*6     0   0   2   0   0
##   *1/*9     0   0   0  10   0
##   *10/*10   0   0  35   0   0
##   *10/*17   0   0   1   0   0
##   *10/*41   0   0   8   0   0
##   *17/*17   0   0   3   0   0
##   *17/*41   0   0   3   0   0
##   *3/*4     3   0   0   0   0
##   *3/*9     0   1   0   0   0
##   *4/*10    0   1   0   0   0
##   *4/*17    0   2   0   0   0
##   *4/*4     2   0   0   0   0
##   *4/*41    0   7   0   0   0
##   *4/*5     3   0   0   0   0
##   *4/*9     0   1   0   0   0
##   *41/*41   0   0   3   0   0
##   *5/*10    0  14   0   0   0
##   *5/*41    0   1   0   0   0
##   *5/*5     1   0   0   0   0
##   *5/*9     0   1   0   0   0
##   *9/*41    0   0   1   0   0
## CYP2D6 allele frequencies:
## 
##   *1  *10  *17   *3   *4  *41   *5   *6   *9 
## 72.1 10.5  3.2  0.5  5.8  3.7  3.1  0.1  1.0
##       
##          0 0.5   1 1.5   2
##   0      6   0   0   0   0
##   0.25   0  15   0   0   0
##   0.5    3  12  35   0   0
##   0.75   0   0   9   0   0
##   1      0   1  96   0   0
##   1.25   0   0   0  56   0
##   1.5    0   0   5  71   0
##   2      0   0   0   0 407
##                Activity Score
## CYP2D6 Genotype   0 0.25 0.5 0.75   1 1.25 1.5   2
##         *1/*1     0    0   0    0   0    0   0 407
##         *1/*10    0    0   0    0   0   56   0   0
##         *1/*17    0    0   0    0   0    0  34   0
##         *1/*3     0    0   0    0   0    0   3   0
##         *1/*4     0    0   0    0  62    0   0   0
##         *1/*41    0    0   0    0   0    0  27   0
##         *1/*5     0    0   0    0  24    0   0   0
##         *1/*6     0    0   0    0   0    0   2   0
##         *1/*9     0    0   0    0   0    0  10   0
##         *10/*10   0    0  35    0   0    0   0   0
##         *10/*17   0    0   0    1   0    0   0   0
##         *10/*41   0    0   0    8   0    0   0   0
##         *17/*17   0    0   0    0   3    0   0   0
##         *17/*41   0    0   0    0   3    0   0   0
##         *3/*4     0    0   3    0   0    0   0   0
##         *3/*9     0    0   0    0   1    0   0   0
##         *4/*10    0    1   0    0   0    0   0   0
##         *4/*17    0    0   2    0   0    0   0   0
##         *4/*4     2    0   0    0   0    0   0   0
##         *4/*41    0    0   7    0   0    0   0   0
##         *4/*5     3    0   0    0   0    0   0   0
##         *4/*9     0    0   1    0   0    0   0   0
##         *41/*41   0    0   0    0   3    0   0   0
##         *5/*10    0   14   0    0   0    0   0   0
##         *5/*41    0    0   1    0   0    0   0   0
##         *5/*5     1    0   0    0   0    0   0   0
##         *5/*9     0    0   1    0   0    0   0   0
##         *9/*41    0    0   0    0   1    0   0   0

Basic data plots

weight

##       country outcome_primary.1 outcome_primary.2
## 1      Brazil                26               156
## 2    Cambodia                50                18
## 3    Colombia                36                11
## 4    Ethiopia                16                25
## 5       India                 0                 9
## 6        Peru                20               162
## 7 Philippines                 0                 3
## 8    Thailand                11                56
## 9     Vietnam                 7                29
##       country outcome_primary.1 outcome_primary.2
## 1      Brazil                35               310
## 2    Cambodia                53                36
## 3    Colombia                25                16
## 4    Ethiopia                25                52
## 5       India                 4                54
## 6        Peru                30               384
## 7 Philippines                17                 6
## 8    Thailand                19               171
## 9     Vietnam                 9                44

##       country weight
## 1    Ethiopia     53
## 2 Philippines     53
## 3    Thailand     54
## 4    Cambodia     55
## 5     Vietnam     57
## 6       India     60
## 7        Peru     62
## 8    Colombia     67
## 9      Brazil     70

Methb data

## There are a total of 9632 mthb measurements in 818 patients
## Between day 0 and day 20 there are 5816 measurements. Median (range) per patient is 7 (1 to 12)

## 
## Call:
## lm(formula = log10(day7_mthb) ~ tqmgkgtot, data = pk_summaries)
## 
## Residuals:
##      Min       1Q   Median       3Q      Max 
## -1.11911 -0.16721  0.00514  0.18448  0.62429 
## 
## Coefficients:
##              Estimate Std. Error t value Pr(>|t|)    
## (Intercept) -0.100671   0.024584  -4.095 4.76e-05 ***
## tqmgkgtot    0.065552   0.004891  13.404  < 2e-16 ***
## ---
## Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
## 
## Residual standard error: 0.2632 on 648 degrees of freedom
##   (72 observations deleted due to missingness)
## Multiple R-squared:  0.2171, Adjusted R-squared:  0.2159 
## F-statistic: 179.7 on 1 and 648 DF,  p-value: < 2.2e-16

## [1] 17.86515
## 
## Call:
## lm(formula = t_12_terminal_rescaled ~ AS_score <= 0.5, data = outcome_dat)
## 
## Residuals:
##    Min     1Q Median     3Q    Max 
## -9.754 -1.990 -0.422  1.425 33.434 
## 
## Coefficients:
##                     Estimate Std. Error t value Pr(>|t|)    
## (Intercept)         18.42601    0.20665  89.166   <2e-16 ***
## AS_score <= 0.5TRUE -0.05197    0.69070  -0.075     0.94    
## ---
## Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
## 
## Residual standard error: 3.899 on 389 degrees of freedom
##   (709 observations deleted due to missingness)
## Multiple R-squared:  1.455e-05,  Adjusted R-squared:  -0.002556 
## F-statistic: 0.005662 on 1 and 389 DF,  p-value: 0.9401

Weight based models of tafenoquine efficacy

Logistic regression

## Using all data (n=1073), the odds ratio for recurrence at 4 months for each additional mg/kg of tafenoquine is 0.7 (95% CI 0.65 to 0.76)
## Using all data (n=1073), the odds ratio for recurrence at 4 months for each additional mg/kg of primaquine is 0.63 (95% CI 0.55 to 0.71)
## Using only patients who got a 300 mg dose (n=469), the odds ratio for recurrence at 4 months for each additional mg/kg of tafenoquine is 0.66 (95% CI 0.51 to 0.86)
## Using all patients (n=1073), the odds ratio for recurrence at 6 months for each additional mg/kg of tafenoquine is 0.72 (95% CI 0.67 to 0.77)
## Using all patients (n=1073), the odds ratio for recurrence at 6 months for each additional mg/kg of primaquine is 0.61 (95% CI 0.54 to 0.69)

EMAX model

load fits

Compare EMAX model fits

Figure 2 in paper: the main mg/kg driving efficacy plot under the EMAX model

## [1] 0.2840664
## [1] 0.2067025
## [1] 0.1415006
## The model estimates that a 15 mg/kg TQ dose reduces 98.64% of all recurrences at 4 months
## The E90 is 7.5 mg/kg
## The E50 is 3.6 mg/kg

## The E95 is 9 mg/kg
## The E90 is 8.4 mg/kg
## The E50 is 3.6 mg/kg

## The E95 is 10.3 mg/kg

dose-response

## [1] "mean efficacies:"
## [1] 68.0794
## [1] 87.81331

compare logistic and EMAX

## (Intercept)   pqmgkgtot   tqmgkgtot    logpara0 
##  -1.3718004  -0.4664881  -0.3510041   0.3632042

weight versus efficacy

## Mean recurrence for 300 mg:
##  2.5%   50% 97.5% 
##  10.2  15.4  21.6
## Mean recurrence for 450 mg:
##  2.5%   50% 97.5% 
##   3.5   6.5  11.2
## Mean recurrence for 600 mg:
##  2.5%   50% 97.5% 
##   0.9   2.9   7.7

## NNT (95%CI):
##  2.5%   50% 97.5% 
##   7.5  11.3  21.1

Compare for different parts of the world

## 
##       Africa     Americas Asia-Pacific 
##           55          724          321
## In Americas the odds ratio for recurrence for each additional mg/kg increase in tafenoquine dose is 0.813 (n=710)
## In Asia-Pacific the odds ratio for recurrence for each additional mg/kg increase in tafenoquine dose is 0.82 (n=311)
## In Africa the odds ratio for recurrence for each additional mg/kg increase in tafenoquine dose is 0.801 (n=52)

Compare all ORs for logistic regression models

AUC

## Using all data (n=634), the odds ratio for recurrence at 6 months for each additional mg/kg of tafenoquine is 0.6 (95% CI 0.46 to 0.76)
## Using all data (n=634), and adjusted for TQ mg/kg dose, the odds ratio for recurrence at 6 months for each SD in TQ AUC 1.02 (95% CI 0.73 to 1.4)
## Using patients who got 300 mg (n=469), the odds ratio for recurrence at 6 months for each additional mg/kg of tafenoquine is 0.9 (95% CI 0.69 to 1.15)

CMAX

## Using all data (n=634), the odds ratio for recurrence at 6 months for each 10 fold increase in tafenoquine CMAX is 0.15 (95% CI 0.06 to 0.32)
## Using all data (n=634), and adjusted for TQ mg/kg dose, the odds ratio for recurrence at 6 months for each SD in TQ Cmax 1.27 (95% CI 0.32 to 4.8)

## Using who got 300 mg (n=469), the odds ratio for recurrence at 6 months for each 10 fold increase in tafenoquine CMAX is 0.07 (95% CI 0.01 to 0.43)

Terminal elimination half-life

## 
## Call:
## lm(formula = t_12_terminal_rescaled ~ log(weight) + country, 
##     data = outcome_dat)
## 
## Residuals:
##    Min     1Q Median     3Q    Max 
## -9.532 -1.975 -0.385  1.432 33.993 
## 
## Coefficients:
##                    Estimate Std. Error t value Pr(>|t|)   
## (Intercept)         9.02208    3.60674   2.501  0.01262 * 
## log(weight)         2.11378    0.83738   2.524  0.01183 * 
## countryCambodia     0.19427    0.93459   0.208  0.83540   
## countryColombia     0.50455    1.07202   0.471  0.63805   
## countryEthiopia    -0.47763    0.80133  -0.596  0.55135   
## countryIndia        0.04244    0.66988   0.063  0.94951   
## countryPeru         1.16167    0.40278   2.884  0.00406 **
## countryPhilippines  1.88886    2.17048   0.870  0.38449   
## countryThailand     0.02899    0.51722   0.056  0.95533   
## countryVietnam      0.30310    0.78000   0.389  0.69771   
## ---
## Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
## 
## Residual standard error: 3.715 on 639 degrees of freedom
##   (451 observations deleted due to missingness)
## Multiple R-squared:  0.03419,    Adjusted R-squared:  0.02059 
## F-statistic: 2.514 on 9 and 639 DF,  p-value: 0.007827

## 
##  Pearson's product-moment correlation
## 
## data:  outcome_dat$weight and outcome_dat$t_12_terminal_rescaled
## t = 3.1948, df = 642, p-value = 0.001468
## alternative hypothesis: true correlation is not equal to 0
## 95 percent confidence interval:
##  0.04830372 0.20041913
## sample estimates:
##       cor 
## 0.1250965
## Using all data (n=629), the odds ratio for recurrence at 4 months for each additional day in the tafenoquine half life is 1.15 (95% CI 1.07 to 1.23)
## Using all data (n=629), the odds ratio for recurrence at 4 months for each additional day in the tafenoquine half life is 1.12 (95% CI 1.04 to 1.21)

## Using patients given 300 mg (n=465), the odds ratio for recurrence at 4 months for each additional day in the tafenoquine half life is 1.17 (95% CI 1.08 to 1.27)

Methaemoglobin

## Using all TQ treated patients (n=569), the odds ratio for recurrence at 4 months for each absolute percentage increase in methaemoglobin is 0.82 (95% CI 0.67 to 0.99)
## Under the TQ mg/kg dose EMAX model, each absolute percentage point increase in methaemglobin as associated in an odds-ratio for recurrence at 4 months of 0.81 (95% CI 0.66 to 0.98)

Everything

## Generalized linear mixed model fit by maximum likelihood (Laplace
##   Approximation) [glmerMod]
##  Family: binomial  ( logit )
## Formula: 
## outcome_primary ~ tqmgkgtot + scale(log(day7_mthb)) + scale(t_12_terminal_rescaled) +  
##     scale(logpara0) + (1 | studysite)
##    Data: outcome_dat
## 
##      AIC      BIC   logLik deviance df.resid 
##    565.2    591.2   -276.6    553.2      560 
## 
## Scaled residuals: 
##     Min      1Q  Median      3Q     Max 
## -1.3830 -0.5449 -0.3822 -0.1585  3.2466 
## 
## Random effects:
##  Groups    Name        Variance Std.Dev.
##  studysite (Intercept) 0.472    0.687   
## Number of obs: 566, groups:  studysite, 20
## 
## Fixed effects:
##                               Estimate Std. Error z value Pr(>|z|)    
## (Intercept)                   -0.27094    0.37047  -0.731 0.464574    
## tqmgkgtot                     -0.27311    0.07582  -3.602 0.000316 ***
## scale(log(day7_mthb))         -0.27274    0.15283  -1.785 0.074328 .  
## scale(t_12_terminal_rescaled)  0.28367    0.11383   2.492 0.012701 *  
## scale(logpara0)                0.16677    0.11812   1.412 0.157972    
## ---
## Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
## 
## Correlation of Fixed Effects:
##             (Intr) tqmgkg s((7_) s(_12_
## tqmgkgtot   -0.772                     
## scl(lg(7_))  0.330 -0.431              
## scl(t_12__) -0.030 -0.030  0.184       
## scal(lgpr0)  0.059 -0.069  0.010  0.109
## Full model has 566 datapoints

Phase 1: relationship with DHA/PQP?

## 
## Call:
## glm(formula = log10(day7_mthb) ~ tqmgkgtot + TYPE, data = pk_summaries)
## 
## Deviance Residuals: 
##     Min       1Q   Median       3Q      Max  
## -1.1253  -0.1679   0.0104   0.1811   0.6181  
## 
## Coefficients:
##              Estimate Std. Error t value Pr(>|t|)    
## (Intercept) -0.151522   0.036502  -4.151 3.75e-05 ***
## tqmgkgtot    0.064592   0.004908  13.161  < 2e-16 ***
## TYPE         0.062112   0.033011   1.882   0.0603 .  
## ---
## Signif. codes:  0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
## 
## (Dispersion parameter for gaussian family taken to be 0.06901405)
## 
##     Null deviance: 57.344  on 649  degrees of freedom
## Residual deviance: 44.652  on 647  degrees of freedom
##   (72 observations deleted due to missingness)
## AIC: 111.87
## 
## Number of Fisher Scoring iterations: 2
## 
##      CQ    None      AL DHA/PQP 
##     578      24      24      24

Power calculations and trial design

Power calculations

Superiority of 450 over 300 mg single dose